Bipyrazole derivatives as JAK inhibitors

Abstract

The present invention provides compounds of Formula I: or pharmaceutically acceptable salts thereof, as well as their compositions and methods of use, that inhibit the activity of Janus kinase (JAK) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

What is claimed is: 
     
       1. A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 Cy 1  is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted by 1, 2, 3, or 4 groups independently selected from R 3 , R 4 , R 5 , and R 6 ; 
 Y is N or CH; 
 R 1  is C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3  alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl-C 1-3  alkyl, phenyl, phenyl-C 1-3  alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C 1-3  alkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, C 1-3  alkyl, —OH, —O(C 1-3  alkyl), —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(C 1-3  alkyl), —N(C 1-3  alkyl) 2 , —C(═O)N(C 1-3  alkyl) 2 , —C(═O)NH(C 1-3  alkyl), —C(═O)NH 2 , —C(═O)O(C 1-3  alkyl), —S(═O) 2 (C 1-3  alkyl), —S(═O) 2 (C 3-6  cycloalkyl), —C(═O)(C 3-6  cycloalkyl), and —C(═O)(C 1-3  alkyl); 
 R 2  is H or C 1-3  alkyl; wherein said C 1-3  alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from fluoro, chloro, —OH, —O(C 1-3  alkyl), —CN, —CF 3 , —CHF 2 , —CH 2 F, NH 2 , —NH(C 1-3  alkyl), and —N(C 1-3  alkyl) 2 ; or 
 R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 4-, 5- or 6-membered heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 substitutents independently selected from F, Cl, —OH, —O(C 1-3  alkyl), —CN, C 1-3  alkyl, C 1-3  haloalkyl, —NH 2 , —NH(C 1-3  alkyl), —N(C 1-3  alkyl) 2 , —CH 2 CN, and —CH 2 OH; 
 R 3  is H, F, Cl, —CN, C 1-3  alkyl, C 1-3  fluoroalkyl, —O(C 1-3  alkyl), or —O(C 1-3  fluoroalkyl); 
 R 4  is H, F, Cl, —CN, C 1-3  alkyl, C 1-3  fluoroalkyl, —O(C 1-3  alkyl), or —OC(C 1-3  fluoroalkyl); 
 R 5  is H, F, Cl, —CN, C 1-3  alkyl, C 1-3  fluoroalkyl, —O(C 1-3  alkyl), or —OC(C 1-3  fluoroalkyl); 
 R 6  is H, F, Cl, —CN, C 1-3  alkyl, C 1-3  fluoroalkyl, —O(C 1-3  alkyl), or —OC(C 1-3  fluoroalkyl); 
 R 7  is H, F, Cl, C 1-3  alkyl, C 1-3  haloalkyl, —NR 17 R 17a , —NHC(═O)R 17b , —C(═O)NR 17a R 17b , —NHS(═O) 2 R 17b , or —S(═O) 2 NR 17a R 17b , wherein said C 1-3  alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, Cl, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , OH, —OCH 3 , —OCF 3 , —OCHF 2 , and —OCH 2 F; 
 R 8  is H, F, Cl, C 1-3  alkyl, or C 1-3  haloalkyl; 
 R 9  is H, F, Cl, C 1-3  alkyl, C 1-3  haloalkyl, cyclopropyl, —CN, —NH 2 , —NH(C 1-3  alkyl), or —N(C 1-3  alkyl) 2 , wherein said C 1-3  alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH; 
 R 10  is H, F, Cl, C 1-3  alkyl, C 1-3  haloalkyl, cyclopropyl, —CN, —NH 2 , —NH(C 1-3  alkyl), or —N(C 1-3  alkyl) 2 , wherein said C 1-3  alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH; 
 R 17  is C 1-6  alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 27  substituents; 
 R 17a  is H or alkyl; 
 R 17b  is C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , OH, —OCH 3 , and —OCF 3 , —OCHF 2 , and —OCH 2 F; and 
 each R 27  is independently selected from halo, —OH, NO 2 , —CN, C 1-3  alkyl, C 2-3  alkenyl, C 2-3  alkynyl, C 1-3  haloalkyl, cyano-C 1-3  alkyl, HO—C 1-3  alkyl, CF 3 —C 1-3  hydroxyalkyl, C 1-3  alkoxy-C 1-3  alkyl, C 3-7  cycloalkyl, C 1-3  alkoxy, C 1-3  haloalkoxy, H 2 N—, (C 1-3  alkyl)NH—, (C 1-3  alkyl) 2 N—, HS—, C 1-3  alkyl-S—, C 1-3  alkyl-S(═O)—, C 1-3  alkyl-S(═O) 2 —, carbamyl, C 1-3  alkylcarbamyl, di(C 1-3  alkyl)carbamyl, carboxy, C 1-3  alkyl-C(═O)—, C 1-4  alkoxy-C(═O)—, C 1-3  alkyl-C(═O)O—, C 1-3  alkyl-C(═O)NH—, C 1-3  alkyl-S(═O) 2 NH—, H 2 N—SO 2 —, C 1-3  alkyl-NH—S(═O) 2 —, (C 1-3  alkyl) 2 N—S(═O) 2 —, H 2 N—S(═O) 2 NH—, C 1-3  alkyl-NHS(═O) 2 NH—, (C 1-3  alkyl) 2 N—S(═O) 2 NH—, H 2 N—C(═O)NH—, C 1-3  alkyl-NHC(═O)NH—, and (C 1-3  alkyl) 2 N—C(═O)NH—. 
 
     
     
       2. The compound of  claim 1 , having Formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound of  claim 1 , having Formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 X is N or CR 4 ; 
 W is N or CR 6 ; 
 Y is N or CH; 
 R 1  is C 1-6  alkyl, C 1-6  haloalkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-3  alkyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkyl-C 1-3  alkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, C 1-3  alkyl, —OH, —O(C 1-3  alkyl), —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(C 1-3  alkyl), —N(C 1-3  alkyl) 2 , —C(═O)N(C 1-3  alkyl) 2 , —C(═O)NH(C 1-3  alkyl), —C(═O)NH 2 , —C(═O)O(C 1-3  alkyl), —S(═O) 2 (C 1-3  alkyl), —S(═O) 2 (C 3-6  cycloalkyl), —C(═O)(C 3-6  cycloalkyl), and —C(═O)(C 1-3  alkyl); 
 R 2  is H or C 1-3  alkyl; wherein said C 1-3  alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from fluoro, chloro, —OH, —O(C 1-3  alkyl), —CN, —CF 3 , —CHF 2 , —CH 2 F, NH 2 , —NH(C 1-3  alkyl), and —N(C 1-3  alkyl) 2 ; or 
 R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 4-, 5- or 6-membered heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 substitutents independently selected from fluoro, —OH, —O(C 1-3  alkyl), —CN, C 1-3  alkyl, C 1-3  haloalkyl, —NH 2 , —NH(C 1-3  alkyl), —N(C 1-3  alkyl) 2 , and —CH 2 CN; 
 R 3  is H, F, Cl, —CN, C 1-3  alkyl, —OCF 3 , —CF 3 , or —O(C 1-3  alkyl); 
 R 4  is H, F, Cl, —CN, C 1-3  alkyl, or —O(C 1-3  alkyl); 
 R 5  is H, F, Cl, —CN, C 1-3  alkyl, or —O(C 1-3  alkyl); 
 R 6  is H, F, CL, —CN, or C 1-3  alkyl; 
 R 7  is H, F, Cl, C 1-3  alkyl, C 1-3  haloalkyl, —NR 17 R 17a , —NHC(═O)R 17b , —C(═O)NR 17a R 17b , —NHS(═O) 2 R 17b , or —S(═O) 2 NR 17a R 17b , wherein said C 1-3  alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, Cl, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH; 
 R 8  is H, F, Cl, C 1-3  alkyl, or C 1-3  haloalkyl; 
 R 9  is H, F, Cl, C 1-3  alkyl, C 1-3  haloalkyl, cyclopropyl, —CN, —NH 2 , —NH(C 1-3  alkyl), or —N(C 1-3  alkyl) 2 , wherein said C 1-3  alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH; 
 R 10  is H, F, Cl, C 1-3  alkyl, C 1-3  haloalkyl, cyclopropyl, —CN, —NH 2 , —NH(C 1-3  alkyl), or —N(C 1-3  alkyl) 2 , wherein said C 1-3  alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH; 
 R 17  is C 1-6  alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 27 ; 
 R 17a  is H or alkyl; 
 R 17b  is C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH and 
 each R 27  is independently selected from halo, —OH, NO 2 , —CN, C 1-3  alkyl, C 2-3  alkenyl, C 2-3  alkynyl, C 1-3  haloalkyl, cyano-C 1-3  alkyl, HO—C 1-3  alkyl, CF 3 —C 1-3  hydroxyalkyl, C 1-3  alkoxy-C 1-3  alkyl, C 3-7  cycloalkyl, C 1-3  alkoxy, C 1-3  haloalkoxy, H 2 N—, (C 1-3  alkyl)NH—, (C 1-3  alkyl) 2 N—, HS—, C 1-3  alkyl-S—, C 1-3  alkyl-S(═O)—, C 1-3  alkyl-S(═O) 2 —, carbamyl, C 1-3  alkylcarbamyl, di(C 1-3  alkyl)carbamyl, carboxy, C 1-3  alkyl-C(═O)—, C 1-4  alkoxy-C(═O)—, C 1-3  alkyl-C(═O)O—, C 1-3  alkyl-C(═O)NH—, C 1-3  alkyl-S(═O) 2 NH—, H 2 N—SO 2 —, C 1-3  alkyl-NH—S(═O) 2 —, (C 1-3  alkyl) 2 N—S(═O) 2 —, H 2 N—S(═O) 2 NH—, C 1-3  alkyl-NHS(═O) 2 NH—, (C 1-3  alkyl) 2 N—S(═O) 2 NH—, H 2 N—C(═O)NH—, C 1-3  alkyl-NHC(═O)NH—, and (C 1-3  alkyl) 2 N—C(═O)NH—. 
 
     
     
       4. The compound of  claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 1-6  alkyl, C 1-6  haloalkyl, C 3-6  cycloalkyl, or C 3-6  cycloalkyl-C 1-3  alkyl, wherein said C 1-6  alkyl, C 3-6  cycloalkyl, and C 3-6  cycloalkyl-C 1-3  alkyl, are each optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, —CF 3 , and methyl; 
 R 2  is H or methyl; 
 R 3  is H, F, or Cl; 
 R 4  is H or F; 
 R 5  is H or F; 
 R 6  is H or F; 
 R 7  is H, methyl, ethyl or HO—CH 2 —; 
 R 8  is H or methyl; 
 R 9  is H, methyl or ethyl; and 
 R 10  is H, methyl, ethyl or HO—CH 2 —. 
 
     
     
       5. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is N. 
     
     
       6. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH. 
     
     
       7. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N. 
     
     
       8. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 4 . 
     
     
       9. The compound of  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 4  is H or F. 
     
     
       10. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is C 1-6  alkyl, C 1-6  haloalkyl, C 3-6  cycloalkyl, or C 3-6  cycloalkyl-C 1-3  alkyl, wherein said C 1-6  alkyl, C 3-6  cycloalkyl, and C 3-6  cycloalkyl-C 1-3  alkyl, are each optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, —CF 3 , and methyl. 
     
     
       11. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is isopropyl, ethyl, 1-methylpropyl, 2,2,2-trifluoro-1-methylethyl, 1-cyclopropylethyl, cyclopropyl, 1-trifluoromethylcyclopropyl, 1-cyclopropyl-2,2,2-trifluoroethyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl. 
     
     
       12. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein having Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       13. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein having Formula III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       14. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein, having Formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       15. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein, having Formula IIa: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       16. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein, having Formula IIIa: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       17. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein, having Formula IVa: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       18. The compound of  claim 1  selected from:
 5-[3-(cyanomethyl)-3-(3′-methyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide; 
 5-[3-(cyanomethyl)-3-(3′-methyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-isopropylpyrazine-2-carboxamide; 
 4-[3-(cyanomethyl)-3-(3′-methyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-isopropylbenzamide; 
 4-[3-(cyanomethyl)-3-(3′-methyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide; 
 4-[3-(1H,1′H-4,4′-Bipyrazol-1-yl)-3-(cyanomethyl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide; 
 5-[3-(cyanomethyl)-3-(3,3′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-isopropylpyrazine-2-carboxamide; 
 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide; 
 5-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-isopropylpyrazine-2-carboxamide; 
 5-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide; 
 5-[3-(cyanomethyl)-3-(3-methyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-isopropylpyrazine-2-carboxamide; 
 5-[3-(cyanomethyl)-3-(3′-ethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide; 
 4-{3-(cyanomethyl)-3-[3′-(hydroxymethyl)-1H,1′H-4,4′-bipyrazol-1-yl]azetidin-1-yl}-2, 5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide; 
 4-{3-(cyanomethyl)-3-[3-(hydroxymethyl)-3′-methyl-1H,1′H-4,4′-bipyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       19. A composition comprising a compound or salt according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       20. A method of inhibiting an activity of JAK1 comprising contacting JAK1 with a compound or salt according to  claim 1 . 
     
     
       21. A method according to  claim 20 , wherein said compound or salt is selective for JAK1 over JAK2. 
     
     
       22. A method of treating a cancer selected from breast cancer, prostate cancer, lung cancer, renal cancer, colorectal cancer, and pancreatic cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound or salt according to  claim 1 . 
     
     
       23. The method of  claim 22 , wherein the cancer is breast cancer. 
     
     
       24. The method of  claim 22 , wherein the cancer is prostate cancer. 
     
     
       25. The method of  claim 22 , wherein the cancer is lung cancer. 
     
     
       26. The method of  claim 22 , wherein the cancer is renal cancer. 
     
     
       27. The method of  claim 22 , wherein the cancer is colorectal cancer. 
     
     
       28. The method of  claim 22 , wherein the cancer is pancreatic cancer. 
     
     
       29. The compound of  claim 1 , which is 5-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
       30. A method of treating a cancer selected from breast cancer, prostate cancer, lung cancer, renal cancer, colorectal cancer, and pancreatic cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound or salt according to  claim 29 .